[Abstract + References] Antidepressant effect of vagal nerve stimulation in epilepsy patients: a systematic review

Abstract

Background

Vagal nerve stimulation (VNS) is an effective palliative therapy in drug-resistant epileptic patients and is also approved as a therapy for treatment-resistant depression. Depression is a frequent comorbidity in epilepsy and it affects the quality of life of patients more than the seizure frequency itself. The aim of this systematic review is to analyze the available literature about the VNS effect on depressive symptoms in epileptic patients.

Material and methods

A comprehensive search of PubMed, Medline, Scopus, and Google Scholar was performed, and results were included up to January 2020. All studies concerning depressive symptom assessment in epileptic patients treated with VNS were included.

Results

Nine studies were included because they fulfilled inclusion criteria. Six out of nine papers reported a positive effect of VNS on depressive symptoms. Eight out of nine studies did not find any correlation between seizure reduction and depressive symptom amelioration, as induced by VNS. Clinical scales for depression, drug regimens, and age of patients were broadly different among the examined studies.

Conclusions

Reviewed studies strongly suggest that VNS ameliorates depressive symptoms in drug-resistant epileptic patients and that the VNS effect on depression is uncorrelated to seizure response. However, more rigorous studies addressing this issue are encouraged.

References

1. 1.Chen Z, Brodie MJ, Liew D, Kwan P (2018) Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs a 30-year longitudinal cohort study. JAMA Neurol 75:279–286. https://doi.org/10.1001/jamaneurol.2017.3949Article PubMed Google Scholar 
2. 2.Spencer S, Huh L (2008) Outcomes of epilepsy surgery in adults and children. Lancet Neurol 7:525–537Article Google Scholar 
3. 3.De Tisi J, Bell GS, Peacock JL et al (2011) The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet 378:1388–1395. https://doi.org/10.1016/S0140-6736(11)60890-8Article PubMed Google Scholar 
4. 4.Rathore C, Radhakrishnan K (2015) Concept of epilepsy surgery and presurgical evaluation. In: Epileptic disorders
5. 5.Benbadis SR, Geller E, Ryvlin P, Schachter S, Wheless J, Doyle W, Vale FL (2018) Putting it all together: options for intractable epilepsy. Epilepsy Behav 88:33–38. https://doi.org/10.1016/j.yebeh.2018.05.030Article Google Scholar 
6. 6.Ben-Menachem E, Mañon-Espaillat R, Ristanovic R et al (1994) Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. Epilepsia 35:616–626. https://doi.org/10.1111/j.1528-1157.1994.tb02482.xCAS Article PubMed Google Scholar 
7. 7.George R, Salinsky M, Kuzniecky R et al (1994) Vagus nerve stimulation for treatment of partial seizures: 3. Long-term follow-up on first 67 patients exiting a controlled study. Epilepsia. https://doi.org/10.1111/j.1528-1157.1994.tb02484.x
8. 8.Elliott RE, Morsi A, Kalhorn SP, Marcus J, Sellin J, Kang M, Silverberg A, Rivera E, Geller E, Carlson C, Devinsky O, Doyle WK (2011) Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: long-term outcomes and predictors of response. Epilepsy Behav 20:57–63. https://doi.org/10.1016/j.yebeh.2010.10.017Article PubMed Google Scholar 
9. 9.Orosz I, McCormick D, Zamponi N, Varadkar S, Feucht M, Parain D, Griens R, Vallée L, Boon P, Rittey C, Jayewardene AK, Bunker M, Arzimanoglou A, Lagae L (2014) Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children. Epilepsia 55:1576–1584. https://doi.org/10.1111/epi.12762Article PubMed Google Scholar 
10. 10.Helmers SL, Wheless JW, Frost M, Gates J, Levisohn P, Tardo C, Conry JA, Yalnizoglu D, Madsen JR (2001) Vagus nerve stimulation therapy in pediatric patients with refractory epilepsy: retrospective study. J Child Neurol 16:843–848. https://doi.org/10.1177/08830738010160111101CAS Article PubMed Google Scholar 
11. 11.Boylan LS, Flint LA, Labovitz DL, Jackson SC, Starner K, Devinsky O (2004) Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy. Neurology 62:258–261. https://doi.org/10.1212/01.WNL.0000103282.62353.85CAS Article PubMed Google Scholar 
12. 12.Kim M, Kim Y-S, Kim D-H, Yang TW, Kwon OY (2018) Major depressive disorder in epilepsy clinics: a meta-analysis. Epilepsy Behav 84:56–69. https://doi.org/10.1016/j.yebeh.2018.04.015Article PubMed Google Scholar 
13. 13.Ajinkya S, Fox J, Lekoubou A (2020) Trends in prevalence and treatment of depressive symptoms in adult patients with epilepsy in the United States. Epilepsy Behav 105:106973. https://doi.org/10.1016/j.yebeh.2020.106973Article PubMed Google Scholar 
14. 14.Tombini M, Assenza G, Quintiliani L, Ricci L, Lanzone J, Ulivi M, di Lazzaro V (2020) Depressive symptoms and difficulties in emotion regulation in adult patients with epilepsy: association with quality of life and stigma. Epilepsy Behav 107:107073Article Google Scholar 
15. 15.Yuan T-F, Li A, Sun X, Arias-Carrión O, Machado S (2016) Vagus nerve stimulation in treating depression: a tale of two stories. Curr Mol Med 16:33–39. https://doi.org/10.2174/1566524016666151222143609CAS Article PubMed Google Scholar 
16. 16.Harden CL, Pulver MC, Ravdin LD, Nikolov B, Halper JP, Labar DR (2000) A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy Behav 1:93–99. https://doi.org/10.1006/ebeh.2000.0046Article PubMed Google Scholar 
17. 17.Elger G, Hoppe C, Falkai P, Rush AJ, Elger CE (2000) Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res 42:203–210. https://doi.org/10.1016/S0920-1211(00)00181-9CAS Article PubMed Google Scholar 
18. 18.Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, Howland R, Kling MA, Rittberg BR, Burke WJ, Rapaport MH, Zajecka J, Nierenberg AA, Husain MM, Ginsberg D, Cooke RG (2005) Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry 58:347–354. https://doi.org/10.1016/j.biopsych.2005.05.025Article PubMed Google Scholar 
19. 19.Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, Nahas Z, Haines S, Simpson RK Jr, Goodman R (2000) Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study∗∗See accompanying Editorial, in this issue. Biol Psychiatry 47:276–286. https://doi.org/10.1016/S0006-3223(99)00304-2CAS Article PubMed Google Scholar 
20. 20.Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM, Lavori P, Howland R, Kling MA, Rittberg B, Carpenter L, Ninan P, Moreno F, Schwartz T, Conway C, Burke M, Barry JJ (2005) Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry 58:355–363. https://doi.org/10.1016/j.biopsych.2005.05.024Article PubMed Google Scholar 
21. 21.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62:e1–e34. https://doi.org/10.1016/j.jclinepi.2009.06.006Article PubMed Google Scholar 
22. 22.Klinkenberg S, van den Bosch CNCJ, Majoie HJM, Aalbers MW, Leenen L, Hendriksen J, Cornips EMJ, Rijkers K, Vles JSH, Aldenkamp AP (2013) Behavioural and cognitive effects during vagus nerve stimulation in children with intractable epilepsy–a randomized controlled trial. Eur J Paediatr Neurol 17:82–90. https://doi.org/10.1016/j.ejpn.2012.07.003Article PubMed Google Scholar 
23. 23.Ryvlin P, Gilliam FG, Nguyen DK, Colicchio G, Iudice A, Tinuper P, Zamponi N, Aguglia U, Wagner L, Minotti L, Stefan H, Boon P, Sadler M, Benna P, Raman P, Perucca E (2014) The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia 55:893–900. https://doi.org/10.1111/epi.12611CAS Article PubMed Google Scholar 
24. 24.Radloff LS (1977) The CES-D Scale. Appl Psychol Meas 1:385–401. https://doi.org/10.1177/014662167700100306Article Google Scholar 
25. 25.Gilliam FG, Barry JJ, Hermann BP, Meador KJ, Vahle V, Kanner AM (2006) Rapid detection of major depression in epilepsy: a multicentre study. Lancet Neurol 5:399–405. https://doi.org/10.1016/S1474-4422(06)70415-XArticle PubMed Google Scholar 
26. 26.Klinkenberg S, Majoie HJM, Van Der Heijden MMAA et al (2012) Vagus nerve stimulation has a positive effect on mood in patients with refractory epilepsy. Clin Neurol Neurosurg 114:336–340. https://doi.org/10.1016/j.clineuro.2011.11.016CAS Article PubMed Google Scholar 
27. 27.Chavel SM, Westerveld M, Spencer S (2003) Long-term outcome of vagus nerve stimulation for refractory partial epilepsy. Epilepsy Behav 4:302–309. https://doi.org/10.1016/S1525-5050(03)00109-4Article PubMed Google Scholar 
28. 28.Hoppe C, Helmstaedter C, Scherrmann J, Elger CE (2001) Self-reported mood changes following 6 months of vagus nerve stimulation in epilepsy patients. Epilepsy Behav 2:335–342. https://doi.org/10.1006/ebeh.2001.0194CAS Article PubMed Google Scholar 
29. 29.Hallböök T, Lundgren J, Stjernqvist K, Blennow G, Strömblad LG, Rosén I (2005) Vagus nerve stimulation in 15 children with therapy resistant epilepsy; its impact on cognition, quality of life, behaviour and mood. Seizure 14:504–513. https://doi.org/10.1016/j.seizure.2005.08.007Article PubMed Google Scholar 
30. 30.Spindler P, Bohlmann K, Straub H-B, Vajkoczy P, Schneider UC (2019) Effects of vagus nerve stimulation on symptoms of depression in patients with difficult-to-treat epilepsy. Seizure 69:77–79. https://doi.org/10.1016/j.seizure.2019.04.001Article PubMed Google Scholar 
31. 31.Ettinger AB, Weisbrot DM, Nolan EE, Gadow KD, Vitale SA, Andriola MR, Lenn NJ, Novak GP, Hermann BP (1998) Symptoms of depression and anxiety in pediatric epilepsy patients. Epilepsia 39:595–599. https://doi.org/10.1111/j.1528-1157.1998.tb01427.xCAS Article PubMed Google Scholar 
32. 32.Kerr MP, Mensah S, Besag F, de Toffol B, Ettinger A, Kanemoto K, Kanner A, Kemp S, Krishnamoorthy E, LaFrance WC Jr, Mula M, Schmitz B, van Elst L, Trollor J, Wilson SJ, International League of Epilepsy (ILAE) Commission on the Neuropsychiatric Aspects of Epilepsy (2011) International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy. Epilepsia 52:2133–2138. https://doi.org/10.1111/j.1528-1167.2011.03276.xArticle PubMed Google Scholar 
33. 33.Tombini M, Assenza G, Quintiliani L, Ricci L, Lanzone J, de Mojà R, Ulivi M, di Lazzaro V (2019) Epilepsy-associated stigma from the perspective of people with epilepsy and the community in Italy. Epilepsy Behav 98:66–72. https://doi.org/10.1016/j.yebeh.2019.06.026Article PubMed Google Scholar 
34. 34.Dussaule C, Bouilleret V (2018) Psychiatric effects of antiepileptic drugs in adults. Gériatrie Psychol Neuropsychiatr du Viellissement 16:181–188. https://doi.org/10.1684/pnv.2018.0733Article Google Scholar 
35. 35.Pisani LR, Nikanorova M, Landmark CJ, Johannessen SI, Pisani F (2018) Specific patient features affect antiepileptic drug therapy decisions: focus on gender, age, and psychiatric comorbidities. Curr Pharm Des 23:5639–5648. https://doi.org/10.2174/1381612823666170926103631CAS Article Google Scholar 
36. 36.Assenza G, Lanzone J, Dubbioso R et al (2020) Thalamic and cortical hyperexcitability in juvenile myoclonic epilepsy. Clin Neurophysiol
37. 37.Pellegrino G, Mecarelli O, Pulitano P, Tombini M, Ricci L, Lanzone J, Brienza M, Davassi C, di Lazzaro V, Assenza G (2018) Eslicarbazepine acetate modulates EEG activity and connectivity in focal epilepsy. Front Neurol 9. https://doi.org/10.3389/fneur.2018.01054
38. 38.Rolle CE, Fonzo GA, Wu W, Toll R, Jha MK, Cooper C, Chin-Fatt C, Pizzagalli DA, Trombello JM, Deckersbach T, Fava M, Weissman MM, Trivedi MH, Etkin A (2020) Cortical connectivity moderators of antidepressant vs placebo treatment response in major depressive disorder. JAMA Psychiatry 94305:397. https://doi.org/10.1001/jamapsychiatry.2019.3867Article Google Scholar 
39. 39.Vecchio F, Miraglia F, Curcio G, Della Marca G, Vollono C, Mazzucchi E, Bramanti P, Rossini PM (2015) Cortical connectivity in fronto-temporal focal epilepsy from EEG analysis: a study via graph theory. Clin Neurophysiol 126:1108–1116. https://doi.org/10.1016/j.clinph.2014.09.019Article PubMed Google Scholar 
40. 40.Vecchio F, Miraglia F, Curcio G, Altavilla R, Scrascia F, Giambattistelli F, Quattrocchi CC, Bramanti P, Vernieri F, Rossini PM (2015) Cortical brain connectivity evaluated by graph theory in dementia: a correlation study between functional and structural data. J Alzheimers Dis 45:745–756. https://doi.org/10.3233/JAD-142484Article PubMed Google Scholar 
41. 41.Parker CS, Clayden JD, Cardoso MJ, Rodionov R, Duncan JS, Scott C, Diehl B, Ourselin S (2018) Structural and effective connectivity in focal epilepsy. NeuroImage Clin 17:943–952. https://doi.org/10.1016/j.nicl.2017.12.020Article PubMed Google Scholar 
42. 42.Saletu B, Anderer P, Saletu-Zyhlarz GM (2010) EEG topography and tomography (LORETA) in diagnosis and pharmacotherapy of depression. Clin EEG Neurosci 41:203–210CAS Article Google Scholar 
43. 43.Zhdanov A, Atluri S, Wong W, Vaghei Y, Daskalakis ZJ, Blumberger DM, Frey BN, Giacobbe P, Lam RW, Milev R, Mueller DJ, Turecki G, Parikh SV, Rotzinger S, Soares CN, Brenner CA, Vila-Rodriguez F, McAndrews MP, Kleffner K, Alonso-Prieto E, Arnott SR, Foster JA, Strother SC, Uher R, Kennedy SH, Farzan F (2020) Use of machine learning for predicting escitalopram treatment outcome from electroencephalography recordings in adult patients with depression. JAMA Netw Open 3:e1918377–e1918377Article Google Scholar 
44. 44.Romero-Osorio Ó, Gil-Tamayo S, Nariño D, Rosselli D (2018) Changes in sleep patterns after vagus nerve stimulation, deep brain stimulation or epilepsy surgery: systematic review of the literature. Seizure 56:4–8. https://doi.org/10.1016/j.seizure.2018.01.022Article PubMed Google Scholar 
45. 45.Murray BJ, Matheson JK, Scammell TE (2001) Effects of vagus nerve stimulation on respiration during sleep. Neurology 57:1523–1524CAS Article Google Scholar 
46. 46.Benca RM, Obermeyer WH, Thisted RA, Gillin JC (1992) Sleep and psychiatric disorders: a meta-analysis. Arch Gen Psychiatry 49:651–668CAS Article Google Scholar 
47. 47.Wu JC, Bunney WE (1990) The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. Am J Psychiatry
48. 48.Tononi G, Cirelli C (2012) Time to be SHY? Some comments on sleep and synaptic homeostasis. Neural Plast 2012:1–12. https://doi.org/10.1155/2012/415250Article Google Scholar 
49. 49.Assenza G, Pellegrino G, Tombini M, di Pino G, di Lazzaro V (2013) Delta waves increase after cortical plasticity induction during wakefulness. Clin Neurophysiol 124:e71–e72. https://doi.org/10.1016/j.clinph.2014.09.029Article Google Scholar 
50. 50.Assenza G, Di Lazzaro V (2015) A useful electroencephalography (EEG) marker of brain plasticity: delta waves. Neural Regen Res 10:1216–1217. https://doi.org/10.4103/1673-5374.162698Article PubMed Google Scholar 
51. 51.Wolf E, Kuhn M, Normann C, Mainberger F, Maier JG, Maywald S, Bredl A, Klöppel S, Biber K, van Calker D, Riemann D, Sterr A, Nissen C (2016) Synaptic plasticity model of therapeutic sleep deprivation in major depression. Sleep Med Rev 30:53–62Article Google Scholar 
52. 52.Sanacora G, Zarate CA, Krystal JH, Manji HK (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7:426–437CAS Article Google Scholar 
53. 53.Di Pino G, Pellegrino G, Capone F et al (2016) Val66Met BDNF polymorphism implies a different way to recover from stroke rather than a worse overall recoverability. Neurorehabil Neural Repair 30:3–8. https://doi.org/10.1177/1545968315583721Article PubMed Google Scholar 
54. 54.Sen S, Duman R, Sanacora G (2008) Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 64:527–532CAS Article Google Scholar 
55. 55.Goldschmied JR, Gehrman P (2019) An integrated model of slow-wave activity and neuroplasticity impairments in major depressive disorder. Curr Psychiatry Rep 21:30Article Google Scholar 
56. 56.O’Leary OF, Ogbonnaya ES, Felice D et al (2018) The vagus nerve modulates BDNF expression and neurogenesis in the hippocampus. Eur Neuropsychopharmacol 28:307–316. https://doi.org/10.1016/j.euroneuro.2017.12.004CAS Article PubMed Google Scholar 
57. 57.Lang UE, Bajbouj M, Gallinat J, Hellweg R (2006) Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation. Psychopharmacology 187:56–59. https://doi.org/10.1007/s00213-006-0399-yCAS Article PubMed Google Scholar 
58. 58.Hays SA, Rennaker RL, Kilgard MP (2013) Targeting plasticity with vagus nerve stimulation to treat neurological disease. Progress in brain research. Elsevier, In, pp 275–299Google Scholar 
59. 59.Capone F, Assenza G, Di Pino G et al (2015) The effect of transcutaneous vagus nerve stimulation on cortical excitability. J Neural Transm 122:679–685. https://doi.org/10.1007/s00702-014-1299-7Article PubMed Google Scholar 
60. 60.Kimberley TJ, Prudente CN, Engineer ND, Pierce D, Tarver B, Cramer SC, Dickie DA, Dawson J (2019) Study protocol for a pivotal randomised study assessing vagus nerve stimulation during rehabilitation for improved upper limb motor function after stroke. Eur Stroke J 4:363–377Article Google Scholar 

Source: https://link.springer.com/article/10.1007/s10072-020-04479-2

[WEB SITE] Vagal Nerve Stimulation Improves Arm Function After Stroke

By Sue Hughes,  February 27, 2017

HOUSTON, Texas — An implanted device that stimulates the vagus nerve has shown promising improvement of arm function in stroke patients in a second small clinical study.

While the primary endpoint — change in functional score after 6 weeks of therapy — was not significantly different between treatment groups, the improvement did appear to become significant after a further 60 days of treatment, as did responder rates.

Lead investigator, Jesse Dawson, MD, University of Glasgow, United Kingdom, reported that the group receiving active stimulation with the device showed a 9-point improvement in upper-limb Fugl-Meyer (UEFM) score at this time point.

Dr Jesse Dawson

“All in all, we feel this is quite promising,” Dr Dawson said. “A 9-point change in this scale is highly likely to be clinically significant.”

This magnitude of change would mean different things for different patients, depending on where they start, he said. “If they start at 20 — which is not much function at all — they might regain some grasp ability so they might be able to carry a plate, for example. If they were in the 30s to start with, they would probably already have the grasp function but they would be able to get back to do more specific tasks.”

The results were presented here at the International Stroke Conference (ISC) 2017.

“Spectacular” Results

Commenting on the study, American Heart Association/American Stroke Association spokesperson, Philip Gorelick, MD, MPH, medical director, Hauenstein Neuroscience Center, Grand Rapids, Michigan, described the results as “pretty spectacular.”

Dr Philip Gorelick

“It is always difficult to know what you are getting with these scales, but when you see jumps like this I think it’s safe to conclude that there is clinical significance. There is probably something real going on,” Dr Gorelick said.

“You must remember that these are chronic patients with moderate to severe arm weakness at 18 months down the line from their stroke,” he added. “We think these patients are finished — they are not going to be doing much with that arm. Obviously this study is exploratory, but this raises a lot of hope.”

A larger trial in 120 patients is now planned.

  

MORE —-> Vagal Nerve Stimulation Improves Arm Function After Stroke

[Abstract] Non electrical and non pharmacological ways of vagus nerve stimulation: Overview, pathways and clinical implications

Vagal nerve stimulation is gaining recognition as an important therapeutic approach especially for non-communicable diseases such as cardiovascular disease (CVD), Depression, Fibromyalgia, Arthritis, Type 2 Diabetes, Alzheimer, and certain types of cancer. In turn, decreased vagal tone its implicated in the prognosis of a wide range of diseases. Afferent vagal stimulation seems to have the key to reset certain pathophysiological states of the body leading to health improvement by reshaping neural networks.

via Non electrical and non pharmacological ways of vagus nerve stimulation: Overview, pathways and clinical implications – Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation

[Abstract + References] Improving Stroke Rehabilitation with Vagus Nerve Stimulation

Abstract

Stroke is a leading cause of neurological damage, with an estimated 795,000 cases reported in the United States each year. A large percentage of patients who suffer a stroke exhibit long-term impairments in motor function. Poststroke rehabilitation in part aims to promote adaptive changes in neural circuits to support recovery of function, but insufficient or maladaptive plasticity often limits benefits. Adjunctive strategies that support plasticity in conjunction with rehabilitation represent a potential means to improve recovery after stroke. Vagus nerve stimulation (VNS) has emerged as one such targeted plasticity strategy, providing phasic activation of neuromodulatory nuclei associated with plasticity. Repeatedly pairing brief bursts of VNS with motor training drives robust, specific plasticity in neural circuits. A number of studies in animal models of stroke and neurological injury demonstrate that VNS paired with rehabilitative training improves recovery of motor function. Moreover, emerging evidence from clinical trials indicates that VNS delivered during rehabilitation promotes functional recovery in stroke patients. Here, we provide a discussion of the existing literature of VNS-based targeted plasticity therapies in the context of stroke and outline challenges for clinical implementation.

References

1. 1.
   Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135:e146–603.CrossRefPubMedPubMedCentralGoogle Scholar
2. 2.
   Dobkin BH. Strategies for stroke rehabilitation. Lancet Neurol. 2004;3:528–36.CrossRefPubMedPubMedCentralGoogle Scholar
3. 3.
   Dobkin BH. Rehabilitation after stroke. N Engl J Med. 2005;352:1677–84.CrossRefPubMedPubMedCentralGoogle Scholar
4. 4.
   Lai S, Studenski S, Duncan PW, Perera S. Persisting consequences of stroke measured by the stroke impact scale. Stroke. 2002;33:1840–4.CrossRefPubMedGoogle Scholar
5. 5.
   Calautti C, Baron J. Functional neuroimaging studies of motor recovery after stroke in adults a review. Stroke. 2003;34:1553–66.CrossRefPubMedGoogle Scholar
6. 6.
   Nudo R, Friel K. Cortical plasticity after stroke: implications for rehabilitation. Rev Neurol. 1999;155:713.PubMedGoogle Scholar
7. 7.
   Zhang J, Meng L, Qin W, Liu N, Shi FD, Yu C. Structural damage and functional reorganization in ipsilesional m1 in well-recovered patients with subcortical stroke. Stroke. 2014;45:788–93.CrossRefPubMedGoogle Scholar
8. 8.
   Liepert J, Miltner W, Bauder H, Sommer M, Dettmers C, Taub E, Weiller C. Motor cortex plasticity during constraint-induced movement therapy in stroke patients. Neurosci Lett. 1998;250:5–8.CrossRefPubMedGoogle Scholar
9. 9.
   Hallett M. Plasticity of the human motor cortex and recovery from stroke. Brain Res Rev. 2001;36:169–74.CrossRefPubMedGoogle Scholar
10. 10.
    Englot DJ, Rolston JD, Wright CW, Hassnain KH, Chang EF. Rates and predictors of seizure freedom with vagus nerve stimulation for intractable epilepsy. Neurosurgery. 2016;79:345–53.CrossRefPubMedGoogle Scholar
11. 11.
    Heck C, Helmers SL, DeGiorgio CM. Vagus nerve stimulation therapy, epilepsy, and device parameters scientific basis and recommendations for use. Neurology. 2002;59:S31–7.CrossRefPubMedGoogle Scholar
12. 12.
    Hays SA. Enhancing rehabilitative therapies with vagus nerve stimulation. Neurotherapeutics. 2016;13(2):382–94.CrossRefPubMedGoogle Scholar
13. 13.
    Hulsey DR, Riley JR, Loerwald KW, Rennaker RL, Kilgard MP, Hays SA. Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation. Exp Neurol. 2016;Google Scholar
14. 14.
    Hulsey DR, Hays SA, Khodaparast N, Ruiz A, Das P, Rennaker RL, Kilgard MP. Reorganization of motor cortex by vagus nerve stimulation requires cholinergic innervation. Brain Stimul. 2016;9(2):174–81.CrossRefPubMedPubMedCentralGoogle Scholar
15. 15.
    Nichols J, Nichols A, Smirnakis S, Engineer N, Kilgard M, Atzori M. Vagus nerve stimulation modulates cortical synchrony and excitability through the activation of muscarinic receptors. Neuroscience. 2011;189:207–14.CrossRefPubMedGoogle Scholar
16. 16.
    Seol GH, Ziburkus J, Huang SY, Song L, Kim IT, Takamiya K, Huganir RL, Lee HK, Kirkwood A. Neuromodulators control the polarity of spike-timing-dependent synaptic plasticity. Neuron. 2007;55:919–29.CrossRefPubMedPubMedCentralGoogle Scholar
17. 17.
    He K, Huertas M, Hong S, Tie X, Hell J, Shouval H, Kirkwood A. Distinct eligibility traces for LTP and LTD in cortical synapses. Neuron. 2015;88:528–38.CrossRefPubMedPubMedCentralGoogle Scholar
18. 18.
    Flood JF, Smith GE, Morley JE. Modulation of memory processing by cholecystokinin: dependence on the vagus nerve. Science. 1987;236:832–4.CrossRefPubMedGoogle Scholar
19. 19.
    Flood JF, Morley JE. Effects of bombesin and gastrin-releasing peptide on memory processing. Brain Res. 1988;460:314–22.CrossRefPubMedGoogle Scholar
20. 20.
    Williams C, Jensen RA. Effects of vagotomy on Leu-enkephalin-induced changes in memory storage processes. Physiol Behav. 1993;54:659–63.CrossRefPubMedGoogle Scholar
21. 21.
    Jensen RA. Modulation of memory storage processes by peripherally acting pharmacological agents. Proc West Pharmacol Soc. 1996;39:85–9.PubMedGoogle Scholar
22. 22.
    Talley CP, Clayborn H, Jewel E, McCarty R, Gold PE. Vagotomy attenuates effects of L-glucose but not of D-glucose on spontaneous alternation performance. Physiol Behav. 2002;77:243–9.CrossRefPubMedGoogle Scholar
23. 23.
    Nogueira PJ, Tomaz C, Williams CL. Contribution of the vagus nerve in mediating the memory-facilitating effects of substance P. Behav Brain Res. 1994;62:165–9.CrossRefPubMedGoogle Scholar
24. 24.
    Clark K, Krahl S, Smith D, Jensen R. Post-training unilateral vagal stimulation enhances retention performance in the rat. Neurobiol Learn Mem. 1995;63:213–6.CrossRefPubMedGoogle Scholar
25. 25.
    Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci. 1999;2:94–8.CrossRefPubMedGoogle Scholar
26. 26.
    Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake JA, Sudanagunta SP, Borland MS, Kilgard MP. Reversing pathological neural activity using targeted plasticity. Nature. 2011;470:101–4.CrossRefPubMedPubMedCentralGoogle Scholar
27. 27.
    Shetake JA, Engineer ND, Vrana WA, Wolf JT, Kilgard MP. Pairing tone trains with vagus nerve stimulation induces temporal plasticity in auditory cortex. Exp Neurol. 2011;233:342–9.CrossRefPubMedGoogle Scholar
28. 28.
    Engineer CT, Engineer ND, Riley JR, Seale JD, Kilgard MP. Pairing speech sounds with vagus nerve stimulation drives stimulus-specific cortical plasticity. Brain Stimul. 2015;8(3):637–44.CrossRefPubMedPubMedCentralGoogle Scholar
29. 29.
    Borland MS, Vrana WA, Moreno NA, Fogarty EA, Buell EP, Sharma P, Engineer CT, Kilgard MP. Cortical map plasticity as a function of vagus nerve stimulation intensity. Brain Stimul. 2016;9:117–23.CrossRefPubMedGoogle Scholar
30. 30.
    Porter BA, Khodaparast N, Fayyaz T, Cheung RJ, Ahmed SS, Vrana WA, Rennaker RL II, Kilgard MP. Repeatedly pairing vagus nerve stimulation with a movement reorganizes primary motor cortex. Cereb Cortex. 2011;22:2365–74.CrossRefPubMedGoogle Scholar
31. 31.
    Khodaparast N, Hays SA, Sloan AM, Fayyaz T, Hulsey DR, Rennaker RL II, Kilgard MP. Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke. Neurorehabil Neural Repair. 2014;28:698–706.CrossRefPubMedPubMedCentralGoogle Scholar
32. 32.
    Hays SA, Khodaparast N, Sloan AM, Fayyaz T, Hulsey DR, Ruiz AD, Pantoja M, Kilgard MP, Rennaker RL II. The bradykinesia assessment task: an automated method to measure forelimb speed in rodents. J Neurosci Methods. 2013;214:52–61.CrossRefPubMedGoogle Scholar
33. 33.
    Khodaparast N, Hays SA, Sloan AM, Hulsey DR, Ruiz A, Pantoja M, Rennaker RL II, Kilgard MP. Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke. Neurobiol Dis. 2013;60:80–8.CrossRefPubMedGoogle Scholar
34. 34.
    Canning CG, Ada L, Adams R, O’Dwyer NJ. Loss of strength contributes more to physical disability after stroke than loss of dexterity. Clin Rehabil. 2004;18:300–8.CrossRefPubMedGoogle Scholar
35. 35.
    Harris JE, Eng JJ. Paretic upper-limb strength best explains arm activity in people with stroke. Phys Ther. 2007;87:88–97.CrossRefPubMedGoogle Scholar
36. 36.
    Hays SA, Khodaparast N, Ruiz A, Sloan AM, Hulsey DR, Rennaker RL, Kilgard MP. The timing and amount of vagus nerve stimulation during rehabilitative training affect post-stroke recovery of forelimb strength. Neuroreport. 2014;25(9):676–82.CrossRefPubMedGoogle Scholar
37. 37.
    Kelly-Hayes M, Beiser A, Kase CS, Scaramucci A, D’Agostino RB, Wolf PA. The influence of gender and age on disability following ischemic stroke: the Framingham study. J Stroke Cerebrovasc Dis. 2003;12:119–26.CrossRefPubMedGoogle Scholar
38. 38.
    Freitas C, Perez J, Knobel M, Tormos JM, Oberman L, Eldaief M, Bashir S, Vernet M, Peña-Gómez C, Pascual-Leone A. Changes in cortical plasticity across the lifespan. Front Aging Neurosci. 2011;3Google Scholar
39. 39.
    Pascual-Leone A, Freitas C, Oberman L, Horvath JC, Halko M, Eldaief M, Bashir S, Vernet M, Shafi M, Westover B. Characterizing brain cortical plasticity and network dynamics across the age-span in health and disease with TMS-EEG and TMS-fMRI. Brain Topogr. 2011;24:302–15.CrossRefPubMedPubMedCentralGoogle Scholar
40. 40.
    Hays SA, Ruiz A, Bethea T, Khodaparast N, Carmel JB, Rennaker RL, Kilgard MP. Vagus nerve stimulation during rehabilitative training enhances recovery of forelimb function after ischemic stroke in aged rats. Neurobiol Aging. 2016;43:111–8.CrossRefPubMedPubMedCentralGoogle Scholar
41. 41.
    Bagg S, Pombo AP, Hopman W. Effect of age on functional outcomes after stroke rehabilitation. Stroke. 2002;33:179–85.CrossRefPubMedGoogle Scholar
42. 42.
    Kwakkel G, Kollen BJ, van der Grond J, Prevo AJH. Probability of regaining dexterity in the flaccid upper limb impact of severity of paresis and time since onset in acute stroke. Stroke. 2003;34:2181–6.CrossRefPubMedGoogle Scholar
43. 43.
    Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci. 2004;24:1245–54.CrossRefPubMedGoogle Scholar
44. 44.
    Teasell R, Bitensky J, Salter K, Bayona NA. The role of timing and intensity of rehabilitation therapies. Top Stroke Rehabil. 2005;12:46.CrossRefPubMedGoogle Scholar
45. 45.
    Salter BK, Hartley BM, Foley BN. Impact of early vs delayed admission to rehabilitation on functional outcomes in persons with stroke. J Rehabil Med. 38, 2006;Google Scholar
46. 46.
    Khodaparast N, Kilgard MP, Casavant R, Ruiz A, Qureshi I, Ganzer PD, Rennaker RL 2nd, Hays SA. Vagus nerve stimulation during rehabilitative training improves forelimb recovery after chronic ischemic stroke in rats. Neurorehabil Neural Repair. 2016;30(7):676–84.CrossRefPubMedGoogle Scholar
47. 47.
    Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450–60.CrossRefPubMedGoogle Scholar
48. 48.
    Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5:53–63.CrossRefPubMedGoogle Scholar
49. 49.
    Krishnamurthi RV, Feigin VL, Forouzanfar MH, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson LM, Truelsen T. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010: findings from the global burden of disease study 2010. Lancet Glob Health. 2013;1:e259–81.CrossRefPubMedPubMedCentralGoogle Scholar
50. 50.
    Auriat AM, Wowk S, Colbourne F. Rehabilitation after intracerebral hemorrhage in rats improves recovery with enhanced dendritic complexity but no effect on cell proliferation. Behav Brain Res. 2010;214:42–7.CrossRefPubMedGoogle Scholar
51. 51.
    M. Santos, A. Pagnussat, R. Mestriner, C. Netto. Motor skill training promotes sensorimotor recovery and increases microtubule-associated protein-2 (MAP-2) immunoreactivity in the motor cortex after intracerebral hemorrhage in the rat. ISRN Neurol 2013. (2013).Google Scholar
52. 52.
    Liang H, Yin Y, Lin T, Guan D, Ma B, Li C, Wang Y, Zhang X. Transplantation of bone marrow stromal cells enhances nerve regeneration of the corticospinal tract and improves recovery of neurological functions in a collagenase-induced rat model of intracerebral hemorrhage. Mol Cells. 2013;36:17–24.CrossRefPubMedPubMedCentralGoogle Scholar
53. 53.
    Hays SA, Khodaparast N, Hulsey DR, Ruiz A, Sloan AM, Rennaker RL II, Kilgard MP. Vagus nerve stimulation during rehabilitative training improves functional recovery after intracerebral hemorrhage. Stroke. 2014;45(10):3097–30100.CrossRefPubMedPubMedCentralGoogle Scholar
54. 54.
    Pruitt D, Schmid A, Kim L, Abe C, Trieu J, Choua C, Hays S, Kilgard M, Rennaker RL II. Vagus nerve stimulation delivered with motor training enhances recovery of function after traumatic brain injury. J Neurotrauma. 2016;33(9):871–9.CrossRefPubMedPubMedCentralGoogle Scholar
55. 55.
    Dawson J, Pierce D, Dixit A, Kimberley TJ, Robertson M, Tarver B, Hilmi O, McLean J, Forbes K, Kilgard MP, Rennaker RL, Cramer SC, Walters M, Engineer N. Safety, feasibility, and efficacy of vagus nerve stimulation paired with upper-limb rehabilitation after ischemic stroke. Stroke. 2016;47:143–50.CrossRefPubMedGoogle Scholar
56. 56.
    Clinical Trials Identifier: NCT01669161, Paired vagus nerve stimulation (VNS) with rehabilitation for upper limb function improvement after stroke. ClinicalTrials. gov. Bethesda: National Library of Medicine (US). https://clinicaltrials.gov/ct2/show/NCT01669161 (2014).
57. 57.
    Dawson J, McGrane F. Vagus nerve stimulation and upper limb rehabilitation. Curr Phys Med Rehabil Rep. 2016;4:186–9.CrossRefGoogle Scholar
58. 58.
    Clinical Trials Identifier: NCT02243020, .VNS during rehabilitation for improved upper limb motor function after stroke. ClinicalTrials. gov. Bethesda: National Library of Medicine (US). https://clinicaltrials.gov/ct2/show/study/NCT02243020 (2014).
59. 59.
    Krahl SE, Senanayake SS, Handforth A. Destruction of peripheral C-fibers does not Alter subsequent vagus nerve stimulation-induced seizure suppression in rats. Epilepsia. 2001;42:586–9.CrossRefPubMedGoogle Scholar
60. 60.
    Ruffoli R, Giorgi FS, Pizzanelli C, Murri L, Paparelli A, Fornai F. The chemical neuroanatomy of vagus nerve stimulation. J Chem Neuroanat. 2011;42:288–96.CrossRefPubMedGoogle Scholar
61. 61.
    Evans M, Verma-Ahuja S, Naritoku D, Espinosa J. Intraoperative human vagus nerve compound action potentials. Acta Neurol Scand. 2004;110:232–8.CrossRefPubMedGoogle Scholar
62. 62.
    T. Verlinden, K. Rijkers, G. Hoogland, A. Herrler. Morphology of the human cervical vagus nerve: implications for vagus nerve stimulation treatment. Acta Neurol Scand. (2015).Google Scholar
63. 63.
    Hammer N, Glätzner J, Feja C, Kühne C, Meixensberger J, Planitzer U, Schleifenbaum S, Tillmann BN, Winkler D. Human vagus nerve branching in the cervical region. PLoS One. 2015;10:e0118006.CrossRefPubMedPubMedCentralGoogle Scholar
64. 64.
    U. Planitzer, N. Hammer, I. Bechmann, J. Glätzner, S. Löffler, R. Möbius, B. N. Tillmann, D. Weise, D. Winkler. Positional relations of the cervical vagus nerve revisited. In: Neuromodulation: technology at the neural interface. (2017).Google Scholar
65. 65.
    Roosevelt RW, Smith DC, Clough RW, Jensen RA, Browning RA. Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat. Brain Res. 2006;1119:124–32.CrossRefPubMedPubMedCentralGoogle Scholar
66. 66.
    Castoro MA, Yoo PB, Hincapie JG, Hamann JJ, Ruble SB, Wolf PD, Grill WM. Excitation properties of the right cervical vagus nerve in adult dogs. Exp Neurol. 2011;227:62–8.CrossRefPubMedGoogle Scholar
67. 67.
    Mollet L, Raedt R, Delbeke J, El Tahry R, Grimonprez A, Dauwe I, De Herdt V, Meurs A, Wadman W, Boon P. Electrophysiological responses from vagus nerve stimulation in rats. Int J Neural Syst. 2013;23:1350027.CrossRefPubMedGoogle Scholar
68. 68.
    Clark K, Smith D, Hassert D, Browning R, Naritoku D, Jensen R. Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat. Neurobiol Learn Mem. 1998;70:364–73.CrossRefPubMedGoogle Scholar
69. 69.
    Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain. Brain Res. 2007;1179:28–34.CrossRefPubMedGoogle Scholar
70. 70.
    Ploughman M, Windle V, MacLellan CL, White N, Doré JJ, Corbett D. Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats. Stroke. 2009;40:1490–5.CrossRefPubMedGoogle Scholar
71. 71.
    Schäbitz W, Berger C, Kollmar R, Seitz M, Tanay E, Kiessling M, Schwab S, Sommer C. Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia. Stroke. 2004;35:992–7.CrossRefPubMedGoogle Scholar
72. 72.
    Dan Y, Poo M. Spike timing-dependent plasticity of neural circuits. Neuron. 2004;44:23–30.CrossRefPubMedGoogle Scholar
73. 73.
    Alvarez-Dieppa AC, Griffin K, Cavalier S, McIntyre CK. Vagus nerve stimulation enhances extinction of conditioned fear in rats and modulates arc protein, CaMKII, and GluN2B-containing NMDA receptors in the basolateral amygdala. Neural Plast. 2016;2016Google Scholar
74. 74.
    Xu T, Yu X, Perlik AJ, Tobin WF, Zweig JA, Tennant K, Jones T, Zuo Y. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature. 2009;462:915–9.CrossRefPubMedPubMedCentralGoogle Scholar
75. 75.
    Ay I, Lu J, Ay H, Gregory Sorensen A. Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia. Neurosci Lett. 2009;459:147–51.CrossRefPubMedGoogle Scholar
76. 76.
    Ay I, Ay H. Ablation of the sphenopalatine ganglion does not attenuate the infarct reducing effect of vagus nerve stimulation. Auton Neurosci. 2013;174:31–5.CrossRefPubMedGoogle Scholar
77. 77.
    Ay I, Nasser R, Simon B, Ay H. Transcutaneous cervical vagus nerve stimulation ameliorates acute ischemic injury in rats. Brain Stimul. 2015;9(2):166–73.CrossRefPubMedPubMedCentralGoogle Scholar

via Improving Stroke Rehabilitation with Vagus Nerve Stimulation | SpringerLink

[Abstract] The interaction of pulse width and current intensity on the extent of cortical plasticity evoked by vagus nerve stimulation.

Abstract

Background

Repeatedly pairing a tone with a brief burst of vagus nerve stimulation (VNS) results in a reorganization of primary auditory cortex (A1). The plasticity-enhancing and memory-enhancing effects of VNS follow an inverted-U response to stimulation intensity, in which moderate intensity currents yield greater effects than low or high intensity currents. It is not known how other stimulation parameters effect the plasticity-enhancing effects of VNS.

Objective

We sought to investigate the effect of pulse-width and intensity on VNS efficacy. Here, we used the extent of plasticity induced by VNS-tone pairing to assess VNS efficacy.

Methods

Rats were exposed to a 9 kHz tone paired to VNS with varying current intensities and pulse widths. Cortical plasticity was measured as changes in the percent of area of primary auditory cortex responding to a range of sounds in VNS-treated rats relative to naïve rats.

Results

We find that a combination of low current intensity (200 μA) and short pulse duration (100 μs) is insufficient to drive cortical plasticity. Increasing the pulse duration to 500 μs results in a reorganization of receptive fields in A1 auditory cortex. The extent of plasticity engaged under these conditions is less than that driven by conditions previously reported to drive robust plasticity (800 μA with 100 μs wide pulses).

Conclusion

These results suggest that the plasticity-enhancing and memory-enhancing effects of VNS follow an inverted-U response of stimulation current that is influenced by pulse width. Furthermore, shorter pulse widths may offer a clinical advantage when determining optimal stimulation current. These findings may facilitate determination of optimal VNS parameters for clinical application.

via The interaction of pulse width and current intensity on the extent of cortical plasticity evoked by vagus nerve stimulation – Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation

[WEB SITE] Epilepsy and Seizures: Practice Essentials, Background, Pathophysiology – Medscape

Epileptic seizures are only one manifestation of neurologic or metabolic diseases. Epileptic seizures have many causes, including a genetic predisposition for certain types of seizures, head trauma, stroke, brain tumors, alcohol or drug withdrawal, repeated episodes of metabolic insults, such as hypoglycemia, and other conditions.

Epilepsy and Seizures

• Author: David Y Ko, MD; Chief Editor: Selim R Benbadis, MD  more…

• Overview
• Presentation
• DDx
• Workup
• Treatment
• Medication

Updated: Nov 19, 2015

• Practice Essentials
• Background
• Pathophysiology
• Etiology
• Epidemiology
• Prognosis
• Patient Education
• Show All

References

Practice Essentials

Epilepsy is defined as a brain disorder characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition.^[1]

Signs and symptoms

The clinical signs and symptoms of seizures depend on the location of the epileptic discharges in the cerebral cortex and the extent and pattern of the propagation of the epileptic discharge in the brain. A key feature of epileptic seizures is their stereotypic nature.

Questions that help clarify the type of seizure include the following:

• Was any warning noted before the spell? If so, what kind of warning occurred?
• What did the patient do during the spell?
• Was the patient able to relate to the environment during the spell and/or does the patient have recollection of the spell?
• How did the patient feel after the spell? How long did it take for the patient to get back to baseline condition?
• How long did the spell last?
• How frequent do the spells occur?
• Are any precipitants associated with the spells?
• Has the patient shown any response to therapy for the spells?

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of epileptic seizures is made by analyzing the patient’s detailed clinical history and by performing ancillary tests for confirmation. Physical examination helps in the diagnosis of specific epileptic syndromes that cause abnormal findings, such as dermatologic abnormalities (eg, patients with intractable generalized tonic-clonic seizures for years are likely to have injuries requiring stitches).

Testing

Potentially useful laboratory tests for patients with suspected epileptic seizures include the following:

• Prolactin levels obtained shortly after a seizure to assess the etiology (epileptic vs nonepileptic) of a spell; levels are typically elevated 3- or 4-fold and more likely to occur with generalized tonic-clonic seizures than with other seizure types; however, the considerable variability of prolactin levels has precluded their routine clinical use
• Serum levels of anticonvulsant agents to determine baseline levels, potential toxicity, lack of efficacy, treatment noncompliance, and/or autoinduction or pharmacokinetic change
• CSF examination in patients with obtundation or in patients in whom meningitis or encephalitis is suspected

Imaging studies

The following 2 imaging studies must be performed after a seizure:

• Neuroimaging evaluation (eg, MRI, CT scanning)
• EEG

The clinical diagnosis can be confirmed by abnormalities on the interictal EEG, but these abnormalities could be present in otherwise healthy individuals, and their absence does not exclude the diagnosis of epilepsy.

Video-EEG monitoring is the standard test for classifying the type of seizure or syndrome or to diagnose pseudoseizures (ie, to establish a definitive diagnosis of spells with impairment of consciousness). This technique is also used to characterize the type of seizure and epileptic syndrome to optimize pharmacologic treatment and for presurgical workup.

See Workup for more detail.

Management

Pharmacotherapy

The goal of treatment is to achieve a seizure-free status without adverse effects. Monotherapy is important, because it decreases the likelihood of adverse effects and avoids drug interactions.

Standard of care for a single, unprovoked seizure is avoidance of typical precipitants (eg, alcohol, sleep deprivation). No anticonvulsants are recommended unless the patient has risk factors for recurrence.

Special situations that require treatment include the following:

• Recurrent unprovoked seizures: The mainstay of therapy is an anticonvulsant; if a patient has had more than 1 seizure, administration of an anticonvulsant is recommended
• Having an abnormal sleep-deprived EEG that includes epileptiform abnormalities and focal slowing, diffuse background slowing, and intermittent diffuse intermixed slowing

Selection of an anticonvulsant medication depends on an accurate diagnosis of the epileptic syndrome. Although some anticonvulsants (eg, lamotrigine, topiramate, valproic acid, zonisamide) have multiple mechanisms of action, and some (eg, phenytoin, carbamazepine, ethosuximide) have only one known mechanism of action, anticonvulsant agents can be divided into large groups based on their mechanisms, as follows:

• Blockers of repetitive activation of the sodium channel: Phenytoin, carbamazepine, oxcarbazepine, lamotrigine, topiramate
• Enhancer of slow inactivation of the sodium channel: Lacosamide, rufinamide
• Gamma aminobutyric acid (GABA)–A receptor enhancers: Phenobarbital, benzodiazepines, clobazam
• NMDA receptor blockers: Felbamate
• AMPA receptor blockers: Perampanel, topiramate
• T-calcium channel blockers: Ethosuximide, valproate
• N- and L-calcium channel blockers: Lamotrigine, topiramate, zonisamide, valproate
• H-current modulators: Gabapentin, lamotrigine
• Blockers of unique binding sites: Gabapentin, levetiracetam
• Carbonic anhydrase inhibitors: Topiramate, zonisamide
• Neuronal potassium channel (KCNQ [Kv7]) opener: Ezogabine

Nonpharmacologic therapy

The following are 2 nonpharmacologic methods in managing patients with seizures:

• A ketogenic diet
• Vagal nerve stimulation

Surgical options

The 2 major kinds of brain surgery for epilepsy are palliative and potentially curative. The use of a vagal nerve stimulator (VNS) for palliative therapy in patients with intractable atonic seizures has reduced the need for anterior callosotomy. Lobectomy and lesionectomy are among several possible curative surgeries.

See Treatment and Medication for more detail.

Next Section: Background

Source: Epilepsy and Seizures: Practice Essentials, Background, Pathophysiology